UDCA reduces the need of liver transplantation and the risk of biliary tract cancer in PSC patients

Primary sclerosing cholangitis (PSC) is a rare, progressive, cholestatic and immune-mediated disease characterized by bile duct inflammation.1 Beginning with multifocal biliary strictures, the inflammation would eventually develop into liver cirrhosis and ultimately liver failure.1 PSC mostly afflicts males and is closely associated with inflammatory bowel disease, particularly ulcerative colitis.2 PSC is also a premalignant disease that often leads to hepatobiliary and colon cancers.2 While PSC patients have a ≤30% mortality rate at 6 years after diagnosis, 40-50% of PSC-related deaths are caused by cancer and 30-40%are caused by liver failure.2 To date, no medical therapy has provided significant PSC improvement and most patients would later require liver transplantation.1

Among the limited available therapies, a naturally occurring hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been established as the first-line therapy in primary biliary cholangitis.2 Mechanically, UDCA increases bile flow and biliary bicarbonate secretion, and has anti-apoptotic effects.2 In addition to decreasing the bile toxicity and reducing the level of toxic bile acids, UDCA also has a direct effect on adaptive immunity through the inhibition of dendritic cells.1 Clinically, PSC patients are often placed on a 3-6 month trial period of UCDA, after which biochemical response and symptomatic benefits, e.g. reduced pruritis, will guide the decision for continued treatment.1 However, the efficacy of UCDA in PSC treatment is inconsistent and its long-term outcomes are largely unknown.2 Four previous meta-analyses have failed to demonstrate survival benefit of UCDA in PSC patients, and the largest multicentre randomized controlled trial to date with 219 patients has failed to demonstrate the survival benefits of UDCA after 15 years of follow-up.2

To elucidate possible links between UDCA, cancer, and mortality risk, researchers from Japan conducted a retrospective study on 325 PSC patients from a nationwide PSC registry. From this population, 86% of the PSC patients were given UDCA and the remaining 26% were given bezafibrate. After a median observation period of 5.1 years, UDCA was observed to be associated with an improvement in liver transplantation-free survival (adjusted HR=0.467, 95% CI: 0.280-0.778; p=0.003) and a reduced risk of developing biliary tract cancer (adjusted HR=0.324, 95% CI: 0.135-0.778; p=0.012). These results remained unchanged with sensitivity analyses.

In addition, an inverse probability treatment weighting-adjusted (IPTW) model was used to further validate the results, showing that the association between UDCA and liver transplantation-free survival remained significant after adjustments (adjusted HR=0.429, 95% CI: 0.245-0.753; p=0.02). However, UDCA was not associated with a reduced risk of developing biliary tract cancer after adjustments (adjusted HR=0.418, 95% CI: 0.158-1.104; p=0.10) which may be attributed to the small sample size of the IPTW model.

Based on these results, UDCA treatment was shown to be significantly associated with a benefit of liver transplantation-free survival and is likely to be associated with a reduction of biliary tract cancer among the Japanese PSC cohort. That said, Dr. Toshihiko Arizumi, Teikyo University School of Medicine, Japan, noted that a prospective, randomized, placebo-controlled, well-designed or powered study of UDCA is extremely unlikely to be conducted in the future as UDCA is already off-patent. Furthermore, despite an apparent unmet medical need in PSC treatment, further therapeutic development in the field is also consistently limited by the protracted clinical course of PSC, a lack of clinical trial participants due to the rarity of PSC, and a missing of surrogate endpoint biomarkers.1 With surmounting difficulty in conducting such large-scale study, Dr. Arizumi concluded that “This retrospective, well-characterized, cohort study would be the best option to demonstrate the clinical benefit of UDCA on the long-term outcomes of patients with PSC.”

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